Familial cancer on a Scottish island.

When the causes of death were determined in 18 relations of a child with Fanconi''s anaemia 10 deaths were found to be due to carcinoma of various organs. Cases of osteogenic sarcoma, leukaemia, and Marfan''s syndrome were also discovered among relatives. The family was from a remote community in the hebrides and there was considerable intermarriage. Suggestive evidence of heterozygosity was found by chromosome analysis.     

Pathophysiology of dyslipidemia and increased cardiovascular risk in HIV lipodystrophy: a model of 'systemic steatosis'

PURPOSE OF REVIEW: This review addresses a syndrome of dyslipidemia and lipodystrophy that has emerged in HIV-infected patients receiving highly active antiretroviral therapy (HAART). The term 'HIV/HAART associated dyslipidemic lipodystrophy (HADL)' describes this syndrome. Although HAART increases patient survival rates, their increased longevity and dyslipidemias place them at risk for cardiovascular disease. Identification of rationally based therapies requires an understanding of the mechanistic basis of HADL. RECENT FINDINGS: A case definition for HIV lipodystrophy, based on age, gender, duration of HIV disease, serum HDL cholesterol and anthropometry, provides high diagnostic sensitivity and specificity. The dyslipidemias, mainly hypercholesterolemia, hypertriglyceridemia and low-plasma HDL cholesterol, among HIV-infected patients in the pre- and post-HAART eras are summarized. Clinical studies of HADL patients show increased lipolysis, which increases free fatty acid transfer to liver for incorporation into lipoprotein triglycerides that are secreted, and to skeletal muscle where they impair normal insulin signaling. A model of HADL that includes preferential lipolysis in femoral-gluteal fat depots is presented. Relevant therapies include those that inhibit lipolysis (niacin) or increase hepatic fatty acid oxidation (fibrates). SUMMARY: HADL is one of several disorders characterized by dyslipidemia, insulin resistance, and lipodystrophy. The relative acuteness of HADL should facilitate identification of the sequence of metabolic changes that gives rise to the syndrome. Current evidence suggests that deranged energy storage in femoral-gluteal and other peripheral sites is important; the molecular details for the derangement are unknown but are under scrutiny by many investigators.     

Two successful pregnancies in a woman with chronic myeloid leukemia exposed to nilotinib during the first trimester of her second pregnancy: case study

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder of unknown etiology and characterized by various clinical manifestations and multiple organ involvement. It has been reported in association with POEMS syndrome and can progress to Kaposi's sarcoma or malignant lymphoma. The disease runs a more aggressive course and a poor prognosis. Optimal therapies have not been well established up to now. We here reported a case of rare MCD complicated with multiple myeloma who received bortezomib and achieved very good remission. To our knowledge, this is the first report on MCD in the setting of multiple myeloma with good response to bortezomib.     

FANCJ: Solving problems in DNA replication

The FANCJ protein (also known as BACH1 and BRIP1) is a DNA helicase that is required to preserve the genetic and structural integrity of the genome in complex eukaryotes. In humans, mutations in FANCJ are associated with the chromosome instability disorder Fanconi's anemia and also with the inherited predisposition early-onset breast cancer. Here I will discuss the contribution of FANCJ to human disease, its role in maintenance of genome stability and some current thoughts on the mechanisms through which this is achieved.     

Successful bone marrow transplant for Fanconi's anaemia.

A 15-year-old boy with Fanconi''s anaemia, who required four units of blood each month, received a bone marrow graft from his 9-year-old brother, who has HLA identical and compatible on mixed lymphocyte reaction. Considerable immunosuppression was used and bacterial infection was prevented by vigorous decontamination in a Vickers-Trexler isolator. After the graft the patient''s blood counts remained satisfactory for nine months, but it took six months before qualitative immune function was normal.     

Absence of Hypersensitivity to Glucocorticoids in Antiretroviral‐associated Lipodystrophy

Objective: The lipodystrophy syndrome, which is associated with the use of antiretroviral drugs in some human immunodeficiency virus (HIV)‐infected individuals, bears a striking similarity to the fat redistribution observed in Cushing's disease. Although urinary free cortisol excretion and glucocorticoid receptor binding affinity are not elevated in subjects with lipodystrophy, glucocorticoid action at the cellular level has not been examined in affected individuals. The objective of this study was to determine whether tissue sensitivity to glucocorticoids is increased in subjects with lipodystrophy taking protease inhibitors. Research Methods and Procedures: Subjects included 11 HIV‐infected men on protease inhibitor therapy with lipodystrophy and 10 control HIV‐infected men not on protease inhibitor therapy and without lipodystrophy. Trunk to extremity fat ratio was measured by DXA. Dexamethasone suppression of peripheral blood mononuclear cell proliferation was measured as an index of tissue sensitivity to glucocorticoid action. Results: Compared with the control group, subjects with lipodystrophy had a significant elevation of the trunk to extremity fat ratio [median (interquartile range): 2.9 (1.3) vs. 1.6 (1.2); p < 0.05]. The concentration of dexamethasone resulting in 50% maximal suppression of proliferation was 11.7 nM (9.3 nM) in subjects with lipodystrophy and 19.6 nM (9.7 nM) in control subjects (p = not significant), and the percentage minimal proliferation was 4% (12%) and 17% (18%) in the two groups, respectively (p = not significant). Discussion: Despite the Cushingoid appearance of affected individuals, these data suggest that body fat redistribution in antiretroviral‐associated lipodystrophy does not arise through an increase in postreceptor glucocorticoid signaling.     

Plasma Levels of Immunoreactive Corticotrophin in Patients with Cushing's Syndrome

Plasma levels of immunoreactive corticotrophin (A.C.T.H.) have been determined in 56 patients with Cushing''s syndrome by means of a homologous radioimmunoassay. In untreated Cushing''s disease (bilateral adrenal hyperplasia due to excessive A.C.T.H. secretion from the pituitary) plasma values ranged from 40 to 200 μμg./ml., between 8 and 10 a.m., compared with a range in normal subjects of 12 to 60 μμg./ml. Considerably raised levels, often above 2,000 μμg./ml., were found in patients with Cushing''s disease after bilateral adrenalectomy. A.C.T.H. concentrations were usually higher in patients with bilateral adrenal hyperplasia associated with ectopic A.C.T.H. production than in patients with untreated Cushing''s disease; whereas plasma A.C.T.H. was undetectable in the presence of an adrenocortical tumour. All patients with Cushing''s syndrome failed to show the normal circadian rhythm of circulating A.C.T.H. levels.     

A Clinical Study of Patients with Coronary Heart Disease Complicated with Hypertriglyceridemic Waist Phenotype

The objective of this study was to investigate the characteristics of coronary lesions in patients with coronary heart disease complicated with hypertriglyceridemic waist phenotype and determine the relation to risk factors. For this purpose, 105 patients with ≥50 % stenosis in one branch of coronary arteries as confirmed by coronary angiography were enrolled. Further, in this regard, 41 cases (i.e., case group) were complicated with hypertriglyceridemic waist phenotype, while 64 patients (i.e., control group) were not complicated with this phenotype. The data show that, as compared with control group, the patients in case group had higher coronary artery scores. The coronary lesions in case group were associated with waist triglycerides index and tumor necrosis factor (TNF)-α; partial regression coefficients were 0.774 (P < 0.001) and 0.250 (P = 0.001), respectively. Therefore, it was concluded that the patients with hypertriglyceridemic waist phenotype had a worse coronary heart disease condition, whereas waist triglycerides index and TNF-α related closely to the severity of coronary lesions.     

Genetic aspects of Sjögren's syndrome

Sjögren's syndrome is a multisystem inflammatory rheumatic disease that is classified into primary and secondary forms, with cardinal features in the eye (keratoconjunctivitis sicca) and mouth (xerostomia). The aetiology behind this autoimmune exocrinopathy is probably multifactorial and influenced by genetic as well as by environmental factors that are as yet unknown. A genetic predisposition to Sjögren's syndrome has been suggested on the basis of familial aggregation, animal models and candidate gene association studies. Recent advances in molecular and genetic methodologies should further our understanding of this complex disease. The present review synthesizes the current state of genetics in Sjögren's syndrome.     

Thematic review series: Adipocyte Biology. Lipodystrophies: windows on adipose biology and metabolism

The lipodystrophies are characterized by loss of adipose tissue in some anatomical sites, frequently with fat accumulation in nonatrophic depots and ectopic sites such as liver and muscle. Molecularly characterized forms include Dunnigan-type familial partial lipodystrophy (FPLD), partial lipodystrophy with mandibuloacral dysplasia (MAD), Berardinelli-Seip congenital generalized lipodystrophy (CGL), and some cases with Barraquer-Simons acquired partial lipodystrophy (APL). The associated mutant gene products include 1) nuclear lamin A in FPLD type 2 and MAD type A; 2) nuclear lamin B2 in APL; 3) nuclear hormone receptor peroxisome proliferator-activated receptor gamma in FPLD type 3; 4) lipid biosynthetic enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 in CGL type 1; 5) integral endoplasmic reticulum membrane protein seipin in CGL type 2; and 6) metalloproteinase ZMPSTE24 in MAD type B. An unresolved question is whether metabolic disturbances are secondary to adipose repartitioning or result from a direct effect of the mutant gene product. Careful analysis of clinical, biochemical, and imaging phenotypes, using an approach called "phenomics," reveals differences between genetically stratified subtypes that can be used to guide basic experiments and to improve our understanding of common clinical entities, such as metabolic syndrome or the partial lipodystrophy syndrome associated with human immunodeficiency virus infection.     

IL-21 and Sjögren's syndrome

Treatment of Sjögren's syndrome is almost entirely symptomatic. A lack of true understanding of the underlying immunological pathology of the disease prevents directed therapy. Interleukin-21 (IL-21) is elevated in the serum of patients with this disease and is expressed by the lymphocytes infiltrating the salivary glands. The known functions of IL-21 in facilitating differentiation, proliferation, and survival of both B and T cells mesh well with the findings in Sjögren's syndrome. Demonstration of IL-21 as a fundamental aspect of the pathophysiology of Sjögren's syndrome could lead to the development of anti-IL-21 therapy for this disease.     

Bilateral nephrectomy for massive pulmonary hemorrhage in Goodpasture's syndrome

A case of Goodpasture''s syndrome is described in which bilateral nephrectomy was undertaken because of massive pulmonary hemorrhage. Similar cases recorded in the literature are reviewed. Various hypotheses to explain the beneficial effects of renal ablation on lung purpura are considered. It is suggested that the pulmonary hemorrhage in Goodpasture''s syndrome is mediated in part by a non-antibody humoral factor with permeability-increasing properties that is released from the nephritic kidney.     

Efficacy and Safety of Pioglitazone in Treatment of a Patient with an Atypical Partial Lipodystrophy Syndrome

ObjectiveTo evaluate the effectiveness and safety of pioglitazone therapy in a patient with an atypical presentation of partial lipodystrophy.MethodsWe present a case report and review the associated literature to put this case in perspective and explain its atypical features.ResultsA 40-year-old woman was referred because of uncontrolled diabetes and dyslipidemia, despite receiving a total daily dose of insulin of 300 U and combination therapy with a statin and a fibrate. On examination, the patient was found to have substantial central and abdominal fat deposition in conjunction with slender arms and legs. The addition of pioglitazone to her therapeutic regimen resulted in a dramatic improvement in glycemic control and in the dyslipidemia. During approximately a 2-year period, the patient’s insulin dose was decreased and was ultimately discontinued. Considerable increases in weight and in waist circumference were observed during this period. Sequencing of candidate genes known to be associated with familial partial lipodystrophy, acquired partial lipodystrophy, and generalized lipodystrophy showed no genetic abnormalities. Magnetic resonance imaging confirmed the presence of significant visceral and subcutaneous abdominal fat deposition, in association with scant fat tissue in the extremities. Her weight decreased after discontinuation of the insulin therapy and institution of dietary counseling.ConclusionThiazolidinediones have been shown to be efficacious in syndromic lipodystrophies, such as familial partial lipodystrophy subtype 2. We report that these pharmaceutical agents may also help improve metabolic variables in atypical lipodystrophy syndromes with no obvious molecular basis. A pronounced weight gain might result from synergism between thiazolidinediones and insulin promoting adipogenesis, which diminished somewhat after discontinuation of insulin therapy. (Endocr Pract. 2007;13:656-661)     

The sicca syndrome in thalassaemia major.

A 20 year old man with beta thalassaemia developed symptoms of the sicca syndrome. His serum contained rheumatoid factor and antinuclear antibodies. A biopsy specimen of labial salivary gland showed large accumulations of haemosiderin within the parenchymal cells of the acini. Although in this case the sicca syndrome could not be definitely distinguished from Sjögren''s syndrome, the patient''s HLA type was not the one usually associated with Sjögren''s syndrome. Histological appearances suggested that the causative factor of the sicca syndrome was iron overload owing to an intensive blood transfusion regimen.     

Nephrotic Syndrome in the Elderly

Though the nephrotic syndrome is generally believed to be uncommon in the elderly, patients aged 60 years or more accounted for 25 out of 100 consecutive adult cases. Six (24%) of these had the minimal change lesion, compared with 16% of the younger adults. The incidence of membranous glomerulonephritis was similar in the two age groups, but proliferative glomerulonephritis was more common in the younger (29%) than in the older group (16%). Amyloidosis did not have a higher incidence in the higher age group. Five of the elderly patients with minimal change lesion were treated with prednisone—in four a complete remission from the nephrotic syndrome followed, while the fifth patient''s course is unknown.These results suggest that, when the patient''s other circumstances allow, the nephrotic syndrome in an elderly patient should be investigated and managed as in younger age groups.     

Lipodystrophy of the extremities. A dominantly inherited syndrome associated with lipatrophic diabetes.

A female patient with the following symptoms has been observed: complete absence of subcutaneous fat on the arms and legs, well developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly and elevated basal metabolic rate. The patient thus exhibited all characteristics of lipatrophic diabetes (Lawrence type of diabetes). The mother and a sister of the patient were found to have the same peculiar appearance and a slight hyperlipidemia but no diabetes mellitus. The combination of this type of partial lipodystrophy with severe hyperlipidemia, insulin resistant diabetes mellitus without ketoacidosis and elevated basal metabolic rate was further observed in 2 unrelated patients without known familial occurrence. Thus partial lipodystrophy of the extremities is another, previously undescribed, syndrome associated with the Lawrence type of diabetes mellitus. In the 1 family the syndrome of lipodystrophy and hyperlipidemia is dominantly inherited. Besides the autosomal recessively inherited syndrome of congenital generalized lipodystrophy there is a heterogenous group of dominantly inherited syndromes with various types of lipodystrophy.     

Ectopic lipid accumulation: A potential cause for metabolic disturbances and a contributor to the alteration of kidney function

Ectopic lipid accumulation is now known to be a mechanism that contributes to organ injury in the context of metabolic diseases. In muscle and liver, accumulation of lipids impairs insulin signaling. This hypothesis accounts for the mechanism of insulin resistance in obesity, type 2 diabetes, aging and lipodystrophy. Increasing data suggest that lipid accumulation in the kidneys could also contribute to the alteration of kidney function in the context of metabolic syndrome and obesity. Furthermore and more unexpectedly, animal models of kidney disease exhibit a decreased adiposity and ectopic lipid redistribution suggesting that kidney disease may be a state of lipodystrophy. However, whether this abnormal lipid partitioning during chronic kidney disease (CKD) may have any functional impact in these tissues needs to be investigated.     

Nephrotic Syndrome in Chronic Lymphocytic Leukaemia

Two patients with chronic lymphocytic leukaemia and the nephrotic syndrome are described in whom deposits were shown in renal glomerular basement membranes in a pattern suggesting immune-complex glomerulonephritis. This renal lesion has been described in one case of squamous carcinoma of the bronchus, in one case of Burkitt''s lymphoma, and in three cases of Hodgkin''s disease though not previously in chronic lymphocytic leukaemia. Immune-complex glomerulonephritis is, however, a recognized finding in mice infected with leukaemogenic viruses     

Drug-induced lipotoxicity: Lipodystrophy associated with HIV-1 infection and antiretroviral treatment

A subset of HIV-1-infected patients undergoing antiretroviral treatment develops a lipodystrophy syndrome. It is characterized by loss of peripheral subcutaneous adipose tissue (face, limbs, buttocks), visceral fat accumulation, and, in some cases, lipomatosis, especially in the dorsocervical area. In addition, these patients show metabolic alterations reminiscent of the metabolic syndrome, particularly dyslipidemia and insulin resistance. These alterations lead to enhanced cardiovascular risk in patients and favor the development of diabetes. Although a complex combination of HIV-1 infection and drug treatment-related events triggers the syndrome, lipotoxicity appears to contribute to the development of the syndrome. Active lipolysis in subcutaneous fat, combined with impaired fat storage capacity in the subcutaneous depot, drive ectopic deposition of lipids, either in the visceral depot or in nonadipose sites. Both hepatic steatosis and increased lipid content in skeletal muscle take place and surely contribute to systemic metabolic alterations, especially insulin resistance. Pancreatic function may also be affected by the exposure to high levels of fatty acids; together with direct effects of antiretroviral drugs, this may contribute to impaired insulin release and a prodiabetic state in the patients. Addressing lipotoxicity as a pathogenic actor in the lipodystrophy syndrome should be considered in strategies for treating and/or preventing the morphological alterations and systemic metabolic disturbances associated with lipodystrophy.     

Frey's syndrome: diagnosis in geriatric dentistry

Frey's syndrome, is characterized by warmth, flushing and sweating of the face, most of time in the preauricular region, initiated by any gustatory stimulus. It is frequently related to parotid surgery. A case of Frey's syndrome in a 81‐year‐old female whose long‐delayed clinical onset post‐parotidectomy is presented.